PROJECT SUMMARY Aneurysmal subarachnoid hemorrhage (SAH) is disproportionately lethal and morbid for young patients, causes extensive long-term disability, and results in significant health-economic burden to society. SAH is a heterogeneous condition. A unique feature of SAH is that, in addition to brain injury, patients can develop an acute and severe systemic illness with multiple extra-cerebral organ dysfunctions and a systemic inflammatory response syndrome. Several recent SAH clinical trials all failed to show therapeutic benefit partly due to the high degree of disease heterogeneity. A major barrier to a therapeutic breakthrough in SAH is the lack of appropriate biomarkers to identify patients most at risk for subsequent injury, complications, and bad outcome in this heterogenous population. Endotypes are biological subtypes defined by distinct pathophysiologic mechanisms that could be identified by corresponding biomarkers. Discovery of novel endotypes has led to major therapeutic breakthroughs in cancer and autoimmune diseases. MicroRNAs (miRs) are a novel class of molecules with ideal characteristics as potential biomarkers for systemic response to SAH because miRs are very stable in blood, very specific in their cells of origin and destination, can modulate biological processes in recipient cells by regulating gene expression, and are known to mediate inflammation and immune function. We have promising preliminary data showing that early increase in blood miR-26a after SAH is associated with favorable long-term outcome and possibly reduced risk for delayed cerebral ischemia (DCI), a major cause of morbidity. We hypothesize that blood miR-26a is an early biomarker for SAH long-term outcome and that miR-26a may modulate systemic inflammatory host response and reduce delayed cerebral ischemia (DCI). We propose to investigate miR-26a as a potential biomarker in an existing SAH patient cohort and biobank while simultaneously recruiting a separate, independent replication SAH cohort for prospective validation of this biomarker. As miRs may function in networks, we will explore the global blood miR transcriptome in a subset of patients to identify possible miR networks associated with SAH outcome and with DCI. To examine biological plausibility of miR- 26a in defining a novel inflammation endotype in SAH, we will explore the relationship between blood miR-26a expression and subsequent manifestations of clinical systemic inflammatory response syndrome and changes in blood inflammatory cytokine levels.